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This prospective, randomized, controlled and double-blinded trial studied whether acupuncture in relation to embryo transfer could increase the ongoing pregnancy rates and live birth rates in women undergoing assisted reproductive therapy. A total of 635 patients undergoing IVF or intracytoplasmic sperm injection (ICSI) were included. In 314 patients, embryo transfer was accompanied by acupuncture according to the principles of traditional Chinese medicine. In the control group, 321 patients received placebo acupuncture using a validated placebo needle. In the acupuncture group and the placebo group, the ongoing pregnancy rates were 27% (95% CI 22–32) and 32% (95% CI 27–37), respectively. Live birth rates were 25% (95% CI 20–30) in the acupuncture group and 30% (95% CI 25–30) in the placebo group. The differences were not statistically significant. These results suggest that acupuncture administered in relation to embryo transfer has no effect on the outcome of IVF and ICSI.
suggested that acupuncture on the day of embryo transfer increased the pregnancy rate, the interest from healthcare workers and patients has been huge. In the following years, several randomized controlled studies have showed a beneficial effect of acupuncture at the time of embryo transfer (
Effect of acupuncture on the outcome of in vitro fertilization and intracytoplasmatic sperm injection: a randomized, prospective, controlled clinical study.
). The differences were irrespective of whether the control group received sham acupuncture (i.e. needling at non-acupuncture points) or no treatment. Moreover, in a review from the Cochrane Collaboration (
), including a total of 1022 patients, showed a significantly higher clinical pregnancy rate favouring the use of acupuncture on the day of embryo transfer (OR 1.5, 95% CI 1.15–1.95). As regards live birth rate, only three trials were available for analysis (
) but the meta-analysis confirmed a significant and beneficial effect on the live birth rate when acupuncture was performed on the day of embryo transfer (OR 1.86, 95% CI 1.27–2.73).
Recently however, the results from two other independent meta-analyses have been published (
). Manheimer and colleagues included seven randomized controlled trials comparing acupuncture either without acupuncture, sham acupuncture or placebo acupuncture (i.e. ‘needling’ at true acupuncture points but no penetration of the skin). As in the Cochrane analysis (
demonstrated a significant improvement in the clinical pregnancy rate. On the contrary, El-Toukhy and colleagues (2008) could not demonstrate an increased clinical pregnancy rate when using the same seven studies as
The purpose of the present study was to assess further – through a large randomized controlled and double-blinded trial – whether acupuncture could be used to increase the ongoing pregnancy and live birth rate using the validated Streitberger placebo acupuncture needle in the control group, thus simulating the acupuncture procedure using the same acupuncture points as in the acupuncture group but without penetrating the skin (
This prospective randomized multicentre study was carried out in the period from October 2005 to October 2006 at four public Danish fertility clinics together performing more than 3000 cycles of IVF and intracytoplasmic sperm injection (ICSI) annually. Patients were consecutively informed verbally about the project at the start of hormonal stimulation. On the day of ovum retrieval, all couples were informed in writing about the project. They were also informed that participation in the study required available embryos for transfer and that each clinic could not include and randomize more than two patients per day. The regional ethical committee of Copenhagen and Frederiksberg, Denmark approved the study (no. KF01276193). Further the study was reported to ClinicalTrials.gov (ID NCT00913354)
Sample size calculations were based on an expected average ongoing pregnancy rate of 30% per embryo transfer. Power calculations anticipated that a 10% difference in this endpoint between the true acupuncture and placebo acupuncture group would require approximately 325 patients in each group with a power of 80% and a P-value of 0.05.
Patients
The inclusion criteria were women ⩽37 years of age, treatment with IVF/ICSI and transfer of one or two embryos in the first, second or third stimulated cycle. Embryo transfer was performed on the second or third day after ovum retrieval.
The exclusion criteria were patients treated with frozen and thawed embryos and patients who in the actual cycle already had received any kind of concomitant treatment, i.e. reflexology or acupuncture at a private clinic.
Written consent was given on the day of embryo transfer from patients who were willing to participate and who fulfilled the inclusion criteria.
Randomization
In order to minimize post-randomization drop-out, patients were randomized to either acupuncture or placebo acupuncture on the morning of embryo transfer when it was apparent that there were suitable embryos for transfer. All patients for transfer were informed that they should contact the clinic in the morning after 8.45 am in order to be informed about the status of their fertilization and embryo development, as well as on the availability of embryos for transfer. Patients called the clinic in random order. The capacity of performing acupuncture/placebo acupuncture was limited to two patients a day at each clinic. Therefore the first two patients that called were informed that they could participate if they wished to. In the case of a couple deciding not to participate, the next couple was asked. The laboratory technicians informed about the number of embryos and the embryo quality. The nurses had no access to this information, but exclusively took care of the clinical arrangements.
The sequence of cluster randomization was based on a computer-generated list. In each of the four clinics, for every group of 40 patients, 20 were randomized to acupuncture and twenty to placebo acupuncture. Nurses did the randomization with the sealed envelope technique and the procedure was performed blinded to both the patients and to the clinician who performed the embryo transfer.
Acupuncture
In the present study, acupuncture and placebo acupuncture was performed by nurses who were authorized professional acupuncturists (DA, HB, JF and JS) or by nurses who before initiation of the study had received thorough instruction and training by the four professional acupuncturists. The acupuncture points were chosen according to traditional Chinese medicine and were identical to the points used in the studies by
. They included DU20, M29, KS6, Mp8 and Le3 before embryo transfer and DU20, Co4, Mp10, M36 and Mp6 after embryo transfer. The same acupuncture points were used in both groups. To ensure the same treatment setting for the two groups, the acupuncture points were surrounded with a rubber-ring and covered with a plastic sheet. The needles were applied bilaterally and the patients rested with the needles for 30 min before and 30 min after embryo transfer.
The acupuncture group used the Carbo needle from the Danish company AcuPharma (Ballerup, Denmark). The tip of the needle is sharp and is inserted into deeper tissue layers. The placebo acupuncture group used the validated Strietberger placebo-needle from the company Asia-Med (Suhl, Germany;
). The needle is not fixed inside the copper handle and its tip is blunt. When the needle touches the skin, it moves inside the handle and appears to be shortened. A pricking sensation is felt by the patient, simulating the puncturing of the skin.
Hormone treatments and IVF/ICSI procedures
All patients were treated according to two well-known protocols. With regard to the long protocol (n = 439), patients started down-regulation with a gonadotrophin-releasing hormone agonist (Synerela, Pfizer; or Suprefact, Sanofi-Aventis) in the mid-luteal phase of the cycle preceding the treatment cycle followed by stimulation with recombinant FSH (rFSH; Puregon, Organon; or Gonal-F, Merck Serono) or highly purified human menopausal gonadotrophin (HMG; Menopur, Ferring). Patients treated in the short protocol (n = 179) initiated rFSH/HMG stimulation on cycle day 3 combined with a gonadotrophin-releasing hormone antagonist (Orgalutran, Organon; or Cetrotide, Merck Serono) when the leading follicle had a diameter of 12–14 mm. In all patients, ovulation was triggered by 6500–10,000 units of human chorionic gonadotrophin (HCG) (Ovitrelle, Merck Serono; or Pregnyl, Organon) 36 h before ovum retrieval. Oocytes were retrieved by ultrasound-guided aspiration using manual suction. ICSI was used as the fertilization method in cases of male factor infertility when the total recovery of motile sperm cells was less than 2 million after a density gradient centrifugation in the present or a previous cycle or in cases of previous fertilization failure during IVF. According to Danish national guidelines (www.fertilitetsselskab.dk), a maximum of two embryos were transferred after 2 or 3 days of culture. Luteal support was given to all patients according to clinical practice in the form of vaginal progesterone 600 mg daily (Progestan; NycoMed, Denmark) from the day of embryo transfer and in the following 2 weeks. Irrespective of positive or negative HCG values, progesterone support was stopped at the time of HCG, which is according to Danish national guidelines. Patients with a positive pregnancy test had an ultrasound scan after 7 weeks of gestation in order to confirm a clinical pregnancy. All participants with a live birth were asked to return a form with information regarding delivery. Complete follow-up of all pregnancies is available.
Study endpoints
The ongoing pregnancy rate was considered as the primary endpoint, but it became possible also to report live births. Secondary endpoints were implantation and pregnancy rate.
Statistics
Numerical data are presented as median (5th, 95th centile) and were compared by the Mann–Whitney U-test or the independent-samples T-test where appropriate. Categorical data were analysed by the chi-squared test. Differences in treatment outcome regarding the primary endpoints are presented in percentage points with corresponding 95% CI using the Wilson procedure with a correction for continuity. Further, the difference between group proportions was calculated for each centre. A chi-squared test was used to test if these were homogenous. Finally, to allow for a possible confounding by centre, a joint estimate of the group difference was calculated as a weighted average of the centre specific differences. A two-sided P-value <0.05 was considered statistically significant. Results from intention-to-treat analyses (ITT, n = 635) are presented in this paper. Treated-per-protocol analyses (TPP, n = 618) were performed as well and gave similar results. The statistical package Statistical Package for Social Sciences version 14 (SPSS, Chicago, IL) and SAS version 9.1 (SAS Institute, Cary, USA) was used for analyses.
Results
In the period from October 2005 to October 2006, a total of 635 patients were randomized to either acupuncture (n = 314) or placebo acupuncture (n = 321) (Figure 1). From the acupuncture group and the placebo group, nine and eight patients, respectively, were not treated per protocol. In both groups, it was realized after randomization that three patients did not fulfil the inclusion criteria. Other reasons were discontinuation of acupuncture/placebo acupuncture, postponement of transfer or cancellation of transfer (Figure 1). Consequently, the acupuncture needle was used per protocol in 305 patients and the placebo needle in 313 patients.
Figure 1Study flow chart. Two patients from each group that were not treated per protocol had an ongoing pregnancy. ITT = intention-to-treat; TPP = treated-per-protocol; ∗ = transfer cancelled due to ovarian hyperstimulation syndrome; ∗∗ = transfer cancelled due to lack of suitable embryos.
Table 1 presents demographic data. Groups were comparable with regard to age, body mass index (BMI), duration of infertility, proportion of primary infertility, causes of infertility and number of previous IVF/ICSI attempts.
Table 1Demographic characteristics.
Characteristic
Acupuncture (n =314)
Placebo (n =321)
Age (years)
31 (26, 37)
31 (26, 36)
Body mass index
22.5 (19, 31)
22.5 (19, 33)
Infertility duration (years)
2.5 (1.0, 6.0)
2.5 (1.0, 5.0)
Primary infertility
215 (68)
233 (73)
Infertility diagnosis
Male factor
125 (40)
131 (41)
Tubal factor
54 (17)
45 (14)
Anovulation
23 (7)
30 (9)
Endometriosis
19 (6)
18 (6)
Combined male/female
40 (13)
42 (13)
Unexplained
53 (17)
55 (17)
Previous IVF/ICSI attempts
0
174 (55)
192 (60)
1
104 (33)
89 (28)
2
36 (11)
39 (12)
3
0 (0)
1 (0)
Values are median (5th, 95th centile) or number (%).
Stimulation characteristics are shown in Table 2. The distribution between long agonist and short antagonist protocol was the same in the two groups, as was the use of rFSH and HMG. IVF was used as fertilization method in 58% and 59% of the couples in the acupuncture and placebo group, respectively. Regarding the number of stimulation days, the total dose of rFSH/HMG used per cycle, the endometrial thickness on the day of HCG and the number of follicles aspirated, the groups are comparable.
Table 2Characteristics of controlled ovarian stimulation.
Parameter
Acupuncture (n =314)
Placebo (n =321)
Stimulation protocol
Long agonist
218 (69)
232 (72)
Short antagonist
96 (31)
89 (28)
Gonadotrophin
rFSH
241 (77)
243 (76)
HMG
65 (21)
74 (23)
Combined
8 (3)
4 (1)
IVF as fertilization method
183 (58)
190 (59)
Days of stimulation
10 (7, 14)
10 (8, 14)
Total units of rFSH
1800 (922, 3981)
1688 (950, 3375)
Endometrial thickness on day of HCG (mm)
9.2 (6.0, 13.0)
9.0 (7.0, 13.0)
Follicles aspirated
10 (3, 20)
10 (4, 22)
Values are number (%) or median (5th, 95th centile). Continuous variables were analysed by the Mann–Whitney U-test unless otherwise stated. Categorical data were analysed by the chi-squared test.
There were no statistically significant differences between the two groups.
HCG = human chorionic gonadotrophin; HMG = human menopausal gonadotrophin.
The number of oocytes retrieved and the cleavage rate did not differ statistically between the groups, but the number of available embryos was higher in the placebo group than in the acupuncture group (median 5, 5th–95th centile 1–14, versus median 4, 5th–95th centile 1–11; P = 0.009; Table 3). The number of patients with single-embryo transfer and double-embryo transfer and the number of patients with transfer of top-quality embryos did not differ between the two groups (Table 3).
As a maximum of two embryos were transferred, the individual implantation rate could only be 0%, 50% or 100%.
0%
212 (68)
208 (65)
NS
50%
30 (10)
36 (11)
100%
71 (23)
76 (24)
Patients with embryos cryopreserved
148 (47)
175 (55)
NS
Embryos cryopreserved
3 (1, 8)
4 (1, 9)
NS
Values are median (5th, 95th centile) or number (%). Continuous variables were analysed by the Mann–Whitney U-test. Categorical data were analysed by the chi-squared test.
NS = not statistically significant.
a Embryo transfer was cancelled in one patient from each group.
b Oocytes fertilized and cleaved per oocytes retrieved.
c Four to six equally sized blastomeres with less than 20% fragmentation and no multinucleation.
d As a maximum of two embryos were transferred, the individual implantation rate could only be 0%, 50% or 100%.
The reproductive outcomes are presented in Table 4. There were no statistically significant differences between the group that received acupuncture versus the placebo group as regards positive HCG (40% versus 46%), clinical pregnancy rate (32% versus 35%), ongoing pregnancy rate (27% versus 32%) and live birth rate (25% versus 30%). The absolute difference in ongoing pregnancy rate between the placebo and true acupuncture group was 4.7% (95% CI −2.6 to 11.9) and the absolute difference in live birth rate was 4.8% (95% CI −2.4 to 11.9,). The absolute difference in live birth rate in each centre was: 1.5% (34/129 and 33/133) (95% CI −9.5 to 12.6) in centre 1 (n = 262), 13.5% (29/86 and 17/84) (95% CI −0.7 to 27.0) in centre 2 (n = 170), −0.9% (24/73 and 23/68) (95% CI −17.2 to 15.2) in centre 3 (n = 141) and 6.6% (9/33 and 6/29) (95% CI −17.1 to 28.6) in centre 4 (n = 62). As indicated by the overlapping of the confidence intervals, the variation across centres in the group differences was not statistically significant (using a chi-squared test with three degrees of freedom). A weighted average of the differences yielded a value of 4.85% (95% CI −2.04 to 11.74). Similarly, the variation across centres in the group differences regarding the ongoing pregnancy rate, was not statistically significant (using a chi-squared test with three degrees of freedom). A weighted average of the differences yielded a value of 4.86% (95% CI −2.17 to 11.90).
Table 4Pregnancies and live births.
Parameter
Acupuncture (n =314)
Placebo (n =321)
Positive HCG
126 (40)
149 (46)
Clinical pregnancy
101 (32)
112 (35)
Ongoing pregnancy
85 (27)
102 (32)
Single gestations
71 (84)
89 (87)
Twin gestations
14 (16)
13 (13)
Live birth
79 (25)
96 (30)
Singletons
68 (86)
84 (88)
Twins
11 (14)
12 (13)
Live birth
25 (20–30)
30 (25–35)
Values are number (%) or% (95% CI). Categorical data were analysed by the chi-squared test.
There were no statistically significant differences between the two groups.
In this large randomized double-blinded placebo-controlled trial, acupuncture on the day of embryo transfer did not improve the ongoing pregnancy rate or the live birth rate as compared with placebo acupuncture. As it has been argued earlier (
), it is remarkable that acupuncture is one of the very few interventions that – in meta-analysis – has been shown to improve both implantation and clinical pregnancy rates after embryo transfer. The remarkable issue is that the pathophysiological basis for such an increase is absolutely speculative, as recently commented by
in a very critical comment on the apparent value of acupuncture in assisted reproduction treatment.
The placebo-controlled randomized trial still remains the gold standard for showing that a treatment has a specific effect over placebo and in the last decade several such trials have been published addressing acupuncture in relation to embryo transfer. Further, two independent recent meta-analyses have found a significant effect of acupuncture on the clinical pregnancy rate after assisted reproduction treatment (
The strengths of the current study are primarily its size, which is almost twice as large as any earlier conducted study. Secondly, this study achieved complete follow-up of all pregnancies and are able to document the number of live births, which is considered to be the optimal endpoint for assisted reproduction treatment. Thirdly, this study used the optimal design by including a placebo procedure. Indeed, acupuncture research has to face the issue of how to define the optimal control group. In the context of controlled trials, a placebo can be defined as a ‘dummy’ treatment without the specific action of the real treatment being investigated. In order to achieve single blinding, the placebo treatment has to be indistinguishable from the real treatment to the patient. It could be argued that studies using sham acupuncture in the control group may not be truly blinded to the patients since the needles are located at wrong acupuncture points. This study used the validated acupuncture placebo needle system developed by
found that 54 felt penetration of the skin with the acupuncture needle and 47 with the placebo needle. More importantly, none of the 60 patients suspected that the skin had not been punctured. In the current trial, both the patients and the clinicians who performed the embryo transfer were blinded to the intervention since the acupuncture points in all cases were surrounded with a rubber-ring and covered with a plastic sheet.
Interestingly, in the most recent and large randomized controlled trial of 370 patients by
, a significantly higher pregnancy rate was found in patients receiving placebo acupuncture compared with the real acupuncture group. In accordance with the current trial, the differences were not statistically significant in relation to ongoing pregnancy rate and live birth rate although there was a trend towards higher rates of ongoing pregnancy and live birth in the placebo group in both studies. The results from both this study and
raise the question whether the non-invasive placebo needle can induce physiological effects like the true needle. It is unlikely that acupressure could give an increase in pregnancy rates compared with no intervention. One argument is that the ongoing pregnancy rate in the placebo acupuncture group in the current study, 32%, is very similar to the overall results from Copenhagen University Hospital Rigshospitalet, where most of the patients were included. In the same time period where the study was conducted, this control group had an ongoing pregnancy rate per transfer of 31% (among 1418 transfers) from January 2005 to December 2006.
added the results of another 94 patients to the existing 1366 patients, which changed the result of this meta-analysis to a non-significant finding (presented as a conference abstract,
found no significant benefit of acupuncture (OR 1.24, 95% CI 0.86–1.77) when restricted to the three studies with highest clinical pregnancy rates in the control groups.
In conclusion, considering that the latest published trial by
) have to be considered. If the results of these 988 patients were added to the meta-analysis, it is unlikely that any evidence for any effect of acupuncture accompanying embryo transfer persists.
References
Benson M.R.
Elkind-Hirsch K.E.
Theall A.
Fong K.
Hogan R.B.
Scott R.T.
Impact of acupuncture before and after embryo transfer on the outcome of in vitro fertilization cycles: a prospective single blind randomized study.
Effect of acupuncture on the outcome of in vitro fertilization and intracytoplasmatic sperm injection: a randomized, prospective, controlled clinical study.
Declaration: The authors report no financial or commercial conflicts of interest.
Footnotes
Dorthe Andersen graduated from Nursery school at Herlev Hospital, University of Copenhagen in 1992. Since December 2000 Dorthe has been working at The Fertility Clinic, The Juliane Marie Centre, Rigshospitalet. In 2004 she passed the Acupunturist exam (Traditional Chinise Medicine) as well as a research course for nurses.
Dorthe Andersen graduated from Nursery school at Herlev Hospital, University of Copenhagen in 1992. Since December 2000 Dorthe has been working at The Fertility Clinic, The Juliane Marie Centre, Rigshospitalet. In 2004 she passed the Acupunturist exam (Traditional Chinise Medicine) as well as a research course for nurses.
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